Surface coatings

ABSTRACT

Described herein are substrate coatings.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.15/724,135, filed Oct. 3, 2017, which claims the benefit of U.S.provisional patent application No. 62/403,562, filed Oct. 3, 2016, theentire disclosure of which is incorporated herein by reference.

SUMMARY

Described herein are substrate coatings. In some embodiments, thesubstrates can be associated with a medical device such as animplantable medical device. Implantable medical devices can include, butare not limited to flat coupons, hypo tubes, wires, woven wires, and/orlaser cut objects. In one embodiment, an implantable medical device canbe a stent.

In some embodiments, coatings can include polydopamine andpolyethyleneimine and an increase positive charge on a surface. In otherembodiments, coatings can include polycatechol. In some embodiments, thepolycatechol can increase positive charge on a surface. In otherembodiments, the polycatechol can increase negative charge on a surface.

Methods are also described for forming the herein described coatings. Inone embodiment, a method can functionalize a surface, such as animplantable medical device surface. The method can include depositing adopamine or dopamine-like compound on the surface. In some embodiments,the method can further include conjugating phosphate containingcompounds onto the surface.

In some embodiments, the coatings described herein can bephosphorylcholine coatings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows one suggested pathway dopamine may react with hydroxylsurface functionality.

FIG. 2 shows dopamine polymerization with reaction of Tris buffer.

FIG. 3 shows a reaction for applying a phosphorylcholine coating to a(poly)dopamine functionalized substrate.

FIG. 4 shows a reaction for applying a phosphorylcholine coating to asilane functionalized substrate.

FIG. 5 shows a reaction for synthesizing a phosphorylcholine coating toa (poly)dopamine functionalized substrate.

FIG. 6 shows a reaction for synthesizing a phosphorylcholine coating toa silane functionalized substrate.

FIG. 7 shows carbodiimide coupling of carboxylic acid functionalizedphosphorylcholine (NOF Lipidure-RC01) to free amines of dopamine.

FIG. 8 shows that the dopamine coating process can eventually lead to apolydopamine coating with a mixture of dopamine derivatives as shown,some of which are amendable to Schiff-base addition (1) or Michaeladdition (2).

DETAILED DESCRIPTION

Described herein are substrate coatings. The coatings can be used forimplantable medical devices.

Implant thrombogenicity continues to be a key issue in the treatment ofneurovascular aneurysms especially with coil assist and flow diversionstents. In general, any foreign implanted material in the parentaneurysmal vessel has a risk of causing thrombosis formation. One way toreduce this risk is to impart a biocompatible surface on the implanteddevice by coating or chemically functionalizing the implant. Coating abraided nitinol stent such as LVIS® (Intraluminal Support Device,MicroVention, Inc., Tustin, Calif.) or FRED® (Flow Re-DirectionEndoluminal Device, MicroVention, Inc., Tustin, Calif.) is not permitteddue to the movement of each wire when the stent is collapsed, thussurface functionalization without locking the wires is necessary.

In one embodiment, surface modification of nitinol is described. Onemethod of surface functionalizing nitinol is through silane chemistry.One possible chemical reactivity scheme that has high adherence to manymaterials is dopamine. Dopamine was elucidated by analysis of theadhesive proteins secreted by mussels for attachment to surfaces. FIG. 1indicates one suggested pathway the dopamine may react with hydroxylsurface functionality. This representation may be largely simplified.However, when using dopamine, the actual substrate may not need to havehydroxyl functionality. The reaction process can yield very complicatedstructures and is in part the reason why many different types ofmaterials can be functionalized with dopamine.

In some embodiments, dopamine can be used to act as a tie layer tofurther react biocompatible molecules or polymers to an implantablemedical device. In some embodiments, the implantable medical device canbe a woven stent platform.

Dopamine is a small molecule which autopolymerizes in aqueous solutionsin the presence of oxygen and basic pH (pH>7). This polymerizationoccurs from the catechol structure of the dopamine molecule. In someembodiments, amine functionality on the dopamine molecule can provide apossibility for modification post polymerization. Furthermore, thedopamine autopolymerization can proceed in a simplistic and robustreaction system compared with other catechols or other types of surfacefunctionalization methods.

In some embodiments, dopamine-like compounds can be used. Thesecompounds can have similar deposition characteristics. In oneembodiment, a dopamine-like compound can be L-Dopa(L-3,4-dihydroxyphenylalanine).

This molecule autopolymerizes in a similar manner to dopamine. In someembodiments, L-Dopa may need a salt to screen the carboxylic acid chargefor successful polymerization. L-Dopa is a molecule which polymerizes inhigh pH aqueous media with exposure to dissolved oxygen or otheroxidizing agent (e.g., ammonium persulfate, sodium periodate, coppersulfate). Another dopamine-like compound is 3,4-dihydroxyphenylaceticacid.

Non-functional catechol can autopolymerize and be deposited in aqueoussolutions similar to dopamine. However, additional components may berequired to allow for post autopolymerization functionalization. In someembodiments, a multifunctional polyamine, branched polyethyleneimine canbe used to add amine functionality for later reactions. Otherembodiments can include difunctional amines such as ethylenediamine,propylenediamine, or multifunctional polyelectrolytes such aspolyallylamine. Adding a multifunctional amine can enable thepolymerization and deposition of the catechol as well as providingamines for post deposition processing.

In some embodiments, branched polyethylenimine can be used in thecatechol reaction process. In some embodiments, a Tris buffer can beused in the reaction of dopamaine (FIG. 2), whereby the addition of Tristo a ring occurs from a Michael addition and/or Schiff base reaction.

In other embodiments, other amine functional materials can be utilizedto impart additional functionality to dopamine and other catecholreaction systems. Other amine functional materials can includephosphorylethanolamine and taurine.

These molecules can react during polymerization with catechols similarlyto Tris buffer as demonstrated in FIG. 2. Adding these functionalmolecules during the polymerization of the catechol can provide at leasttwo benefits. First, these molecules are charged at physiological pH andthus may add hydrophilicity to the polycatechol coating. Secondly, thefunctional molecule can be added concomitantly with the polymerization,therefore, a secondary reaction may not be necessary.

In some embodiments, catechol/amine technology is described as astandalone coating method for vessel occluding devices, whereby theincreased amine content can act as a biological binding agent todecrease the time to occlusion for vessel occluding devices.

Positively charged surfaces on implanted materials can cause benefitsand detractions for medical devices. In some embodiments, positivecharged polyallylamine coatings on stainless steel can increase plateletadherence, platelet activation, and fibrinogen adsorption. Theseinteractions can then be quenched by subsequent modification of thepolyallylamine coating. In some embodiments, the interactions can bequenched with heparin. These platelet and fibrinogen type reactions canbe deleterious for stent applications where vessel patency is anecessity. However, these characteristics can be used for vesselocclusion. In one embodiment, a vessel occluding devices may be coatedwith polydopamine and PEI to increase the content of positive chargedamines on the surface.

Other embodiments provide for the attachment of phosphate containingcompounds to any substrate that has been functionalized with dopamine,(poly)dopamine, and/or silane chemistry. Phosphorylcholine contains aphosphate group and can be directly reacted to an amine functionalizedsubstrate. Other phosphate containing molecules can also be reacted tothe dopamine, (poly)dopamine, and/or silane functionalized substratethen used as an intermediate to synthesize phosphorylcholine.

A substrate's material composition can be any metallic/alloy (to includebut is not limited to nitinol, stainless steel, cobalt chromium), anyplastic/polymer (to include but is not limited to grilamide, Pbax,PEEK), or any glass surfaces.

The substrates can be in virtually any form. In one embodiment, thesubstrate is formed into an implantable medical device. In otherembodiments, the substrates may be in the form of a flat coupon, hypotube, wire, woven wire, or laser cut object. In one embodiment, thesubstrate may be formed into a stent such as a braided stent platform.

In some embodiments, the phosphate containing compound can be anycompound containing a phosphate or cyclic phosphate group. Thesecompounds can include, but are not limited to phosphorylcholine and2-chloro-2-oxo-1,3,2-dioxaphospholane.

In other embodiments, carbodiimide molecules can be any carbodiimideincluding, but is not limited to 1-ethyl-3-(3-dimethylamineopropyl)carbodiimide (EDC).

In some embodiments, molecules containing phosphate groups may beconjugated to amine-containing molecules via a carbodiimide reaction.The carbodiimide can activate the phosphate to an intermediate phosphateester. In the presence of an amine, the ester can react to form a stablephosphoramidate bond. Such a reaction scheme can be to immerse the aminefunctionalized material in a phosphorylcholine solution (i.e. water,saline, buffer solution or any applicable organic solvent) containingEDC. Substrate can be incubated in the reaction mixture. Uponcompletion, any non-reacted started materials can be removed by a seriesof washing steps and drying. See FIG. 3 and FIG. 4.

In another embodiment, 2-chloro-2-oxo-1,3,2-dioxaphospholane (COP) canbe reacted with available amines in the presence of TEA to form asubstrate/COP intermediate. The intermediate structure can further betreated with trimethylamine to synthesize a phosphorylcholine richsurface. Any unreactive materials can be removed by a series of washingsteps. See FIG. 5 and FIG. 6.

In some embodiments, the above listed technologies can be used as a tielayer for subsequent functionalizing an implantable medical device withphosphorylcholine (polydopamine, polydopamine w/polyethylenimine,L-Dopa) or as a one-step coating (dopamine, L-Dopa, or catechol combinedw/phosphorylethanolamine or taurine). In one embodiment, thetechnologies can be used to passivate the surface of a MicroVentionFRED® device.

In one embodiment, a reaction scheme can be to immerse the completedassembled woven stent in a water or buffer (Tris, Bicine, Phosphate,etc.) solution containing dopamine (1 mg/ml) at a pH of 7.5-10.5. Thereaction can be protected from UV light and done at room temperature to60° C. for 1 to 24 hrs. The resulting woven stents can then be rinsedwith copious amounts of water and dried in a vacuum oven or inert gasoven at elevated temperature or room temp.

The resulting coated stent can then be amendable to three types offurther surface modification: carbodiimide condensation of dopamine freeamines with carboxylic acid (FIG. 7), reaction with thiols or aminesthrough Michael addition, or Schiff base formation (FIG. 8). FIG. 7displays a carbodiimide coupling of a phosphorylcholine molecule (NOFLipidure-RC01), a cell wall mimic that has shown to greatly improve thebiocompatibility of stents and other implant devices. FIG. 4 displays afew of the intermediate chemical species present during an initialdeposition of dopamine. Some of the final structures may be reactive tothiol or amine functional materials such as polymers, macromers andsmall molecules.

Dopamine coatings may be insensitive to substrate type and/or robustwith regards to high adhesion. This surface functionalization can alsohave the flexibility of accepting many different secondary reactions inwhich a biocompatible functionality may be imparted through reactionswith small molecules, macromers, or polymers.

In some embodiments, an amine rich coating as described herein mayinduce a faster occlusion time when compared with a non-coated device.The occlusion time can be increased by about 5%, about 10%, about 15%,about 20%, about 25%, about 30%, about 35%, about 40%, about 45%, about50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%,about 85%, about 90%, about 95%, about 100%, between about 5% to about35%, or between about 35% to about 65%, when compared to a non-coateddevice.

In other embodiments, the surface composition/coating can include anincrease in atomic nitrogen concentration of about 4% in the treatedstate when compared to an untreated surface. In some embodiments, theincrease in the atomic nitrogen concentration can be about 0.5%, about1%, about 2%, about 4%, about 5%, about 6%, about 7%, about 8%, about9%, about 10%, about 20%, about 30%, about 40%, about 50%, more than50%, between about 0.5% to about 4.5%, or between about 1% to about 10%in the treated state when compared with the untreated surface.

In some embodiments, the treated surfaces of the devices can delay peakthrombin generation time. In some embodiments, the treated surfaces candelay the peak thrombin generation time by about 5%, about 10%, about15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%,about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about80%, about 85%, about 90%, about 95%, about 100%, between about 5% toabout 35%, between about 35% to about 65%, between about 65% to about100% when compared to an untreated surface of a device.

In other embodiments, the treated surfaces of the devices can decreasethe peak thrombin concentration at the treated surface when compared toan untreated surface. In some embodiments, the treated surfaces candecrease the peak thrombin concentration by about 5%, about 10%, about15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45%,about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about80%, about 85%, about 90%, about 95%, about 100%, between about 5% toabout 35%, between about 35% to about 65%, between about 65% to about100% when compared to an untreated surface.

Example 1

Electropolished nitinol test coupons were initially coated toinvestigate the amount of amine deposited on the surface withpolydopamine/PEI and polydopamine/tris(hydroxymethyl)aminomethane(TRIS)/PEI solutions. Reaction buffers were dissolved as listed in TableI. Samples were incubated for 4 hrs at room temperature. The coatingcomposition was determined with x-ray photoelectron spectroscopy (XPS)(Table II). XPS determines the atomic concentration for the top 10 nm ofmaterial. Therefore, a thicker coating will completely block the signalfrom titanium and nickel. The polydopamine/PEI-high had the highestnitrogen to carbon ratio, an indicator that the coating, althoughthinner than the others, would have the highest surface charge comparedto the other reactions. Thus, polydopamine/PEI-high reaction conditionswere chosen to coat occluder devices, but increasing the reaction timeto 16-18 hrs to create a thicker coating.

TABLE I Nitinol coupon deposition solution conditions PEI TRIS DopamineSample (mM) (mM) (mM) Polydopamine/PEI-Low 4.1 mM — 21.1Polydopamine/PEI-High  20 mM — Polydopamine/TRIS/PEI 4.1 mM 10 mM

TABLE II XPS results in atomic concentrations (Atomic %) Sample C N O NaSi S Cl Ca Ti Ni Polydopamine/ 59.0 15.3 21.4 1.4 — — 0.4 — 1.9 0.6PEI-Low Polydopamine/ 33.7 10.3 37.9 0.2 — — 0.2 — 14.0 3.7 PEI-HighPolydopamine/ 64.1 16.6 17.9 — 0.5 0.2 0.1 — 0.5 0.3 TRIS/PEI

Vessel occluder devices were composed of a braided Nitinol wire basketwith an expanded PTFE membrane covering the cross-section of the device.

The devices were coated with a polydopamine/PEI-High solution as listedin Table I, incubating overnight for 16-18 hrs on a rocker at roomtemperature. The coated devices were then loaded and used as normal.

An 8 mm occluder was implanted in a 5.3 mm branch of the R. Subclavianartery of a swine. The device occluded the vessel abruptly after beingimplanted for 3 minutes. The average occlusion time for 6 non-coateddevices was approximately 7 minutes. These initial results indicate thepositive amine rich coating may induce a faster occlusion time whencompared with an uncoated device.

Example 2 Polycatechol Functionalized Nitinol Coupons for SubsequentPhosphorylcholine Polymer Attachment

Electropolished and nitric acid passivated test coupons were coated withan L-Dopa/Bicine solution. Briefly, a 2 mg/mL L-Dopamine solution wasdissolved in a bicine buffer (10 mM Bicine, 0.25 M NaCL, pH 8.5). Thenitric acid passivated coupons were agitated in the L-dopamine solutionfor 18 hrs. Dried samples were then incubated for 18 hrs in a 0.1 M2-(N-morpholino)ethanesulfonic acid buffer containing 0.7 wt % aminefunctional phosphorylcholine polymer (Lipidure-NH01, NOF) and 1.0%1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide.

The surface composition was determined using XPS Table III. The presenceof a phosphorylcholine polymer is indicated by the increase inconcentration of phosphorus on the surface, and decrease in the basematerial nickel and titanium percentages.

TABLE III XPS results in atomic concentrations (Atomic %) C N O Na Si PS Cl K Ca Ti Ni Un- 19.8 1.3 52.1 — 0.3 — 0.5 — — — 21.2 4.9 treatedTreated 34.8 5.5 43.1 4.4 0.7 1.8 0.6 0.4 0.8 0.2 6.2 1.7

Phosphorylcholine coatings are known to increase the blood compatibilityof medical devices. To this end, the treated samples were tested using athrombin generation assay (Thrombinoscope, Diagnostica Stago) using amodified thrombogram test method. Briefly, 300 μL of platelet poorcitrated human plasma was added to each well of a 96 well plate. Testcoupons were loaded into individual wells. Calibration wells were usedto determine the concentration of thrombin generated. Time to peak(ttPeak) thrombin generation and peak thrombin generation can be seen inTable IV. The treated surfaces delayed the peak thrombin generation timeand decreased the peak thrombin concentration to near that of a blankwell indicating the treated samples may have increased bloodcompatibility.

TABLE IV Thrombogram results for coated nitinol materials Peak (nM)ttPeak (min) Untreated 597 ± 74  9.5 ± 0.4 Treated 216 ± 61 23.7 ± 3.9Blank Well 187 ± 22 29.6 ± 3.1

Unless otherwise indicated, all numbers expressing quantities ofingredients, properties such as molecular weight, reaction conditions,and so forth used in the specification and claims are to be understoodas being modified in all instances by the term “about.” Accordingly,unless indicated to the contrary, the numerical parameters set forth inthe specification and attached claims are approximations that may varydepending upon the desired properties sought to be obtained by thepresent invention. At the very least, and not as an attempt to limit theapplication of the doctrine of equivalents to the scope of the claims,each numerical parameter should at least be construed in light of thenumber of reported significant digits and by applying ordinary roundingtechniques. Notwithstanding that the numerical ranges and parameterssetting forth the broad scope of the invention are approximations, thenumerical values set forth in the specific examples are reported asprecisely as possible. Any numerical value, however, inherently containscertain errors necessarily resulting from the standard deviation foundin their respective testing measurements.

The terms “a,” “an,” “the” and similar referents used in the context ofdescribing the invention (especially in the context of the followingclaims) are to be construed to cover both the singular and the plural,unless otherwise indicated herein or clearly contradicted by context.Recitation of ranges of values herein is merely intended to serve as ashorthand method of referring individually to each separate valuefalling within the range. Unless otherwise indicated herein, eachindividual value is incorporated into the specification as if it wereindividually recited herein. All methods described herein can beperformed in any suitable order unless otherwise indicated herein orotherwise clearly contradicted by context. The use of any and allexamples, or exemplary language (e.g., “such as”) provided herein isintended merely to better illuminate the invention and does not pose alimitation on the scope of the invention otherwise claimed. No languagein the specification should be construed as indicating any non-claimedelement essential to the practice of the invention.

Groupings of alternative elements or embodiments of the inventiondisclosed herein are not to be construed as limitations. Each groupmember may be referred to and claimed individually or in any combinationwith other members of the group or other elements found herein. It isanticipated that one or more members of a group may be included in, ordeleted from, a group for reasons of convenience and/or patentability.When any such inclusion or deletion occurs, the specification is deemedto contain the group as modified thus fulfilling the written descriptionof all Markush groups used in the appended claims.

Certain embodiments of this invention are described herein, includingthe best mode known to the inventors for carrying out the invention. Ofcourse, variations on these described embodiments will become apparentto those of ordinary skill in the art upon reading the foregoingdescription. The inventor expects skilled artisans to employ suchvariations as appropriate, and the inventors intend for the invention tobe practiced otherwise than specifically described herein. Accordingly,this invention includes all modifications and equivalents of the subjectmatter recited in the claims appended hereto as permitted by applicablelaw. Moreover, any combination of the above-described elements in allpossible variations thereof is encompassed by the invention unlessotherwise indicated herein or otherwise clearly contradicted by context.

Furthermore, numerous references have been made to patents and printedpublications throughout this specification. Each of the above-citedreferences and printed publications are individually incorporated hereinby reference in their entirety.

In closing, it is to be understood that the embodiments of the inventiondisclosed herein are illustrative of the principles of the presentinvention. Other modifications that may be employed are within the scopeof the invention. Thus, by way of example, but not of limitation,alternative configurations of the present invention may be utilized inaccordance with the teachings herein. Accordingly, the present inventionis not limited to that precisely as shown and described.

1-7. (canceled)
 8. An implantable device including a coating, whereinthe coating includes: a dopamine or dopamine-like compound; and aprimary amine zwitterion.
 9. The implantable device of claim 8, whereinthe dopamine or dopamine-like compound increases positive charge on theimplantable device.
 10. The implantable device of claim 8, wherein thedopamine or dopamine-like compound increases negative charge on theimplantable device.
 11. The implantable device of claim 8, wherein thecoating induces a faster occlusion time when compared to a non-coateddevice.
 12. The implantable device of claim 8, wherein the implantabledevice is a flat coupon, a hypo tube, a wire, a woven wire, a stent, ora laser cut object.
 13. The implantable device of claim 8, wherein theimplantable device is a stent.
 14. (canceled)
 15. The implantable deviceof claim 8, wherein the coating further includes a diamine,multifunctional amine, or multifunctional amine polymer.
 16. (canceled)17. The implantable device of claim 8, wherein the coating furtherincludes a phosphate containing compounds.
 18. The implantable device ofclaim 8, wherein the coating further includes phosphorylcholine.
 19. Theimplantable device of claim 8, wherein the dopamine or dopamine-likecompound is


20. The implantable device of claim 8, wherein the primary aminezwitterion is phosphorylethanolamine.
 21. The implantable device ofclaim 8, wherein the primary amine zwitterion is taurine.